Extramammary Paget Disease

Slide 1 · Extramammary Paget Disease

Vulvar pathology: clinical appearance, morphology, diagnosis and biologic behavior

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Recognize the clinical and microscopic pattern of vulvar Paget disease.

Explain the utility of mucin stains and CK7 in its evaluation.

Differentiate intraepidermal disease from invasive disease and major mimics.

Relate lateral epidermal spread to excision and long-term behavior.

Slide 3 · Vulvar epithelial tumors: Orient the differential

Vulvar epithelial lesions

Squamous-type lesions

Glandular / adnexal lesions

Extramammary Paget disease

Two distinct differentiation patterns; Paget disease belongs in the glandular-type differential.

Slide 4 · The vulva contains modified apocrine glands

The vulva contains modified apocrine-type structures with breastlike features.

This anatomic context helps explain glandular-type vulvar tumors.

Robbins groups Paget disease with other vulvar glandular lesions.

Slide 5 · Definition: Malignant cells within epidermis

Paget disease is a distinctive intraepithelial proliferation of malignant cells.

The malignant glandular-type cells occupy otherwise squamous epidermis.

An intraepidermal location does not itself establish dermal invasion.

Surface

Epidermis

Dermis

Schematic — not a tissue image

Slide 6 · The Paget cell is not an ordinary keratinocyte

Affected cells differ from surrounding squamous keratinocytes.

They appear large, with pale mucin-containing cytoplasm.

These differences create the recognizable histologic pattern.

Surface

Epidermis

Dermis

Schematic — not a tissue image

Slide 7 · Intraepithelial disease is an anatomic designation

Intraepithelial: Malignant cells remain above the basement membrane.

Invasive: Malignant cells extend into underlying stroma.

This distinction is biologically and prognostically important.

Surface

Epidermis

Dermis

Schematic — not a tissue image

Slide 8 · The labia majora are a typical clinical site

Vulvar Paget disease often presents on the labia majora.

The lesion is primarily a superficial skin abnormality.

Site and appearance guide biopsy but cannot replace histology.

Pruritic erythematous plaque (schematic)

Slide 9 · A characteristic clinical triad

Pruritus is a prominent symptom.

The lesion is erythematous and crusted.

A maplike, irregular plaque is a classic description.

Pruritic erythematous plaque (schematic)

Slide 10 · Why the gross contour can mislead

A visible red plaque shows the clinically apparent component.

Paget cells may extend laterally beyond its visible perimeter.

Gross boundaries and microscopic boundaries are not equivalent.

Dashed outline: Conceptual microscopic extent

Slide 11 · The clinical differential begins with dermatitis

An eczematous vulvar patch is not specific for neoplasia.

Inflammatory skin conditions can resemble its surface appearance.

Persistent or atypical lesions require histologic assessment.

Pruritic erythematous plaque (schematic)

Slide 12 · Clinical appearance cannot demonstrate invasion

Color, itch and crusting reflect surface pathology.

Invasion requires evaluation of the epidermal–dermal interface.

A biopsy provides the tissue architecture needed for assessment.

Surface

Epidermis

Dermis

Schematic — not a tissue image

Slide 13 · Low-power H&E: Scan the epidermis

First identify the surface epidermis and underlying dermis.

Look for pale enlarged cells scattered within squamous epithelium.

Preserve the orientation of the dermoepidermal junction.

Surface

Epidermis

Dermis

Schematic — not a tissue image

Slide 14 · The basal epidermis is an important search zone

Paget cells may be concentrated in the lower epidermis.

Scattered pale cells are easier to miss near the basal region.

Review the lower epidermis deliberately at scanning magnification.

Surface

Epidermis

Dermis

Schematic — not a tissue image

Slide 15 · Single-cell pagetoid distribution

Large tumor cells may occur singly among keratinocytes.

The single-cell pattern is a diagnostic clue, not proof by itself.

Correlate cytology with mucin and epithelial immunophenotype.

Surface

Epidermis

Dermis

Schematic — not a tissue image

Slide 16 · Small clusters are also characteristic

Paget cells may form small intraepidermal groups.

Clusters show the same pale cytoplasm as solitary cells.

An epidermal cluster should prompt review of the underlying stroma.

Surface

Epidermis

Dermis

Schematic — not a tissue image

Slide 17 · The tumor cells exceed keratinocytes in size

Relative cell size is more useful than any absolute measurement.

Large pale neoplastic cells interrupt a background of smaller keratinocytes.

Atypical cells are recognized by pattern and cytology together.

Surface

Epidermis

Dermis

Schematic — not a tissue image

Slide 18 · Pale cytoplasm provides the first lineage clue

The cytoplasm often appears pale on routine sections.

It contains mucopolysaccharide material highlighted by special stains.

A pale-cell morphology alone is not tumor-specific.

Surface

Epidermis

Dermis

Schematic — not a tissue image

Slide 19 · Pagetoid spread may extend upward

Although basal growth is common, cells can occupy higher epidermal levels.

The location of malignant cells is an architectural feature.

Higher-level spread still need not imply dermal invasion.

Surface

Epidermis

Dermis

Schematic — not a tissue image

Slide 20 · The dermis may be inflamed beneath the lesion

Inflammation in the dermis under affected epidermis.

An inflammatory infiltrate is not equivalent to malignant invasion.

Distinguish reactive dermal cells from displaced malignant epithelial cells.

Surface

Epidermis

Dermis

Schematic — not a tissue image

Slide 21 · Separate epidermal and stromal compartments

The basement membrane defines the epidermis–dermis boundary.

Intraepidermal Paget cells lie above that boundary.

Demonstrating actual tumor in stroma changes the classification.

Surface

Epidermis

Dermis

Schematic — not a tissue image

Slide 22 · Invasion: The key pathologic question

Microscopically identify malignant epithelial cells beyond the epidermis.

Assess the underlying dermis rather than equating extensive epidermal spread with invasion.

The uncommon invasive cases with poor prognosis.

Surface

Epidermis

Dermis

Conceptual dermal invasion shown

Schematic — not a tissue image

Slide 23 · Surface spread and vertical spread are different

Lateral spread extends the intraepidermal field horizontally.

Vertical stromal invasion crosses the basement membrane.

The two dimensions answer different clinical questions.

Surface

Epidermis

Dermis

Schematic — not a tissue image

Slide 24 · The pale cytoplasm contains mucopolysaccharide

Mucinous material explains why special stains are useful.

The finding supports non-squamous differentiation of Paget cells.

Its interpretation remains contingent on cell location and morphology.

Mucin-containing cytoplasm

PAS highlights mucopolysaccharide

Slide 25 · Periodic acid–Schiff (PAS) stain

PAS as a stain for Paget-cell mucopolysaccharide.

A positive reaction supports intracytoplasmic mucinous material.

It cannot, in isolation, establish the entire diagnosis.

Mucin-containing cytoplasm

PAS highlights mucopolysaccharide

Slide 26 · Alcian blue highlights mucin

Alcian blue is an alternative method to demonstrate mucin.

Its role is supportive alongside H&E morphology.

Mucin-containing cytoplasm

Alcian blue highlights mucin

Slide 27 · Mucicarmine: A third mucin method

Mucicarmine can highlight mucin in Paget cells.

The special stain demonstrates a cell product, not invasion status.

Interpret the positive cells within their epithelial compartment.

Mucin-containing cytoplasm

Mucicarmine highlights mucin

Slide 28 · How to interpret the three mucin stains

Test

What it addresses

Interpretive limitation

PAS

Mucopolysaccharide in Paget-cell cytoplasm

Requires compatible morphology

Alcian blue

Mucinous cytoplasmic material

Not a stand-alone tumor classification

Mucicarmine

Mucin within Paget cells

Does not distinguish in situ from invasion

Slide 29 · Cytokeratin 7 is a defining useful marker

Paget cells express cytokeratin 7 (CK7).

Ordinary surrounding squamous epithelium contrasts with this expression.

CK7 highlights a glandular-type intraepidermal cell population.

Surface

Epidermis

Dermis

CK7-positive Paget cells

Slide 30 · CK7 can reveal subtle pagetoid distribution

Immunostaining makes single cells and clusters easier to localize.

The staining pattern assists assessment of lateral epithelial extent.

CK7 is an adjunct to the H&E architectural evaluation.

Paget epithelial cell

CK7 immunolabeling

Slide 31 · Positive CK7 is not the entire differential

Some mimics require additional lineage markers.

A CK7-positive cell must still be evaluated in its morphologic context.

The differential is resolved through an integrated panel, not one stain.

Surface

Epidermis

Dermis

CK7-positive Paget cells

Slide 32 · Morphology, mucin and CK7: Combined reasoning

Observation

Evidence contributed

What it does not prove

H&E

Pagetoid malignant cell morphology and location

Exact lineage in every case

Mucin stain

Mucopolysaccharide production

Dermal invasion

CK7

Epithelial immunophenotype and cell mapping

Primary versus secondary origin

Slide 33 · Ultrastructural differentiation is mixed

Apocrine, eccrine and keratinocyte differentiation.

The phenotype suggests biologic plasticity of these cells.

This does not require every case to reproduce each feature.

Slide 34 · The proposed cell of origin is a hypothesis

Multipotent cells in mammary gland–like vulvar ducts.

The wording is presumptive, not proof of an established origin.

Do not equate this proposal with demonstrated causation.

Slide 35 · Paget disease is a pattern shared across sites

Mammary and extramammary disease share pagetoid epidermal morphology.

Their usual relationships to underlying carcinoma differ.

A histologic image without anatomic context cannot establish the site.

Surface

Epidermis

Dermis

Schematic — not a tissue image

Slide 36 · Vulvar versus mammary Paget disease

Feature

Vulvar Paget disease

Mammary Paget disease

Typical site

Vulvar epidermis; Often labia majora

Nipple–areolar epidermis

Association

Often no underlying cancer

Associated with ductal breast carcinoma

Anatomic model

Intraepithelial vulvar tumor

Tumor spread from ducts toward nipple skin

Shared pattern

Large pale epidermal Paget cells

Large pale epidermal Paget cells

Slide 37 · Mammary Paget: Connection to ductal carcinoma

In breast, Paget cells extend from ductal carcinoma in situ.

Cells migrate through lactiferous ducts into nipple epidermis.

The neoplastic cells can remain above the basement membrane.

Slide 38 · Vulvar Paget: Association is different

That vulvar Paget disease often lacks underlying cancer.

Most cases are confined to vulvar epidermis.

The contrast is typical, not a statement that associations are impossible.

Surface

Epidermis

Dermis

Schematic — not a tissue image

Slide 39 · An associated internal malignancy remains a consideration

Some extramammary Paget presentations relate to underlying internal cancer.

Primary skin disease and secondary epidermal involvement are different questions.

Site-specific evaluation must follow the actual clinical findings.

Slide 40 · The main microscopic mimics are lineage-defined

Pagetoid melanoma may place atypical cells within epidermis.

Squamous cell carcinoma in situ may also show intraepithelial atypia.

Ancillary markers help establish melanocytic versus squamous versus glandular lineage.

Surface

Epidermis

Dermis

Schematic — not a tissue image

Slide 41 · Melanoma in situ: A major pagetoid mimic

Melanocytic lesions can contain atypical intraepidermal cells.

Paget disease expresses epithelial keratins; Melanoma is typically melanocytic-marker positive.

Use a panel with morphology rather than an isolated marker.

Surface

Epidermis

Dermis

Schematic — not a tissue image

Slide 42 · Squamous cell carcinoma in situ: Key contrast

Squamous intraepithelial carcinoma reflects a keratinocyte phenotype.

P63 supports squamous differentiation, whereas mucin favors Paget cells.

CK7 alone is not sufficient to exclude squamous intraepithelial carcinoma.

Surface

Epidermis

Dermis

Schematic — not a tissue image

Slide 43 · Pagetoid differential: Practical immunophenotype

Feature

Paget disease

Melanoma in situ

SCC in situ

Cell identity

Glandular-type epithelial

Melanocytic

Squamous

Useful supportive stain

CK7 and mucin stains

S100 / SOX10 or Melan-A

P63 / p40

Interpretation

Integrate cells and site

Exclude epithelial mimic

Account for CK7 overlap

Slide 44 · The eczema-like appearance is a diagnostic trap

Clinical inflammation can resemble the crusted pruritic plaque.

Histologic pagetoid malignant cells distinguish the neoplasm.

Failure to assess a persistent lesion can delay recognition.

Pruritic erythematous plaque (schematic)

Slide 45 · Papillary hidradenoma is glandular but different

Papillary hidradenoma is a circumscribed vulvar nodule.

Its papillae contain luminal secretory and basal myoepithelial cells.

Paget disease instead consists of malignant cells within epidermis.

Slide 46 · Two vulvar glandular-type lesions

Feature

Extramammary Paget

Papillary hidradenoma

Clinical tendency

Crusted/pruritic plaque

Circumscribed nodule

Main compartment

Epidermis

Dermal glandular tumor

Microscopic pattern

Single cells and clusters

Papillary projections; Dual cell layer

Management logic

Address occult lateral spread

Assess localized nodular lesion

Slide 47 · Squamous vulvar neoplasia is a separate pathway

VIN and invasive SCC are squamous epithelial neoplasms.

Paget disease has characteristic mucinous pale epithelial cells.

Do not automatically apply HPV-driven squamous tumor biology to Paget disease.

Slide 48 · Diagnostic sequence: Pattern before immunostains

Identify an atypical intraepidermal pale-cell population.

Confirm glandular-type differentiation with CK7 and mucin, as needed.

Use additional markers when the pagetoid differential remains open.

Slide 49 · Diagnostic sequence: Decide whether invasion exists

Review the epidermal–dermal interface carefully.

Separate intraepidermal malignant cells from stromal cells.

Describe true dermal involvement when supported by tissue findings.

Surface

Epidermis

Dermis

Conceptual dermal invasion shown

Schematic — not a tissue image

Slide 50 · Microscopic lateral spread can be invisible

Paget cells may extend beyond the grossly affected skin.

The pathologic boundary may exceed the red, crusted plaque.

This is the rationale for careful excision planning.

Dashed outline: Conceptual microscopic extent

Slide 51 · Excision margin assessment follows cell distribution

Lateral epidermal involvement is a practical margin issue.

A specimen needs orientation and careful edge evaluation.

Clear-looking skin does not, by itself, establish a negative margin.

Surface

Epidermis

Dermis

Schematic — not a tissue image

Slide 52 · Wide local excision addresses occult spread

Wide local excision as treatment.

The justification is microscopically extensive lateral epidermal spread.

Histopathologic mapping and margins matter for local clearance.

Dashed outline: Conceptual microscopic extent

Slide 53 · A long intraepidermal course is possible

Disease restricted to epidermis may persist for years or decades.

Persistence does not necessarily imply early invasion.

Prolonged local disease still carries a clinical burden.

Surface

Epidermis

Dermis

Schematic — not a tissue image

Slide 54 · Dermal invasion is uncommon but consequential

Invasive progression as rare.

Prognosis becomes poor when invasion develops.

Separate long-lasting in situ disease from the invasive subset.

Surface

Epidermis

Dermis

Conceptual dermal invasion shown

Schematic — not a tissue image

Slide 55 · Avoid misinterpreting the word malignant

Paget cells are malignant even when confined to epidermis.

Malignancy and stromal invasion are not synonymous.

Precise reports should state epithelial confinement or invasion.

Surface

Epidermis

Dermis

Schematic — not a tissue image

Slide 56 · Four clinical questions answer different things

Question

Tissue or clinical evidence

Clinical consequence

Where is the disease?

Site and lesion mapping

Directs examination and sampling

What cells are present?

H&E, mucin, CK7 ± differential panel

Defines the lesion

Does it invade?

Epidermal–dermal interface

Changes biologic interpretation

How far does it extend?

Lesion extent and margins

Informs excision

Slide 57 · Case 1: A persistent vulvar plaque

A patient has a slowly enlarging, pruritic, red, crusted lesion of the labia majora. The clinical border is irregular.

What diagnosis belongs in the differential?

What additional assessment is necessary?

Pruritic erythematous plaque (schematic)

Slide 58 · Case 2: Atypical cells within epidermis

Biopsy shows large pale cells, singly and in small groups, among the squamous epidermal keratinocytes. The underlying dermis is inflamed.

Name the characteristic architecture.

Does inflammation alone prove invasion?

Surface

Epidermis

Dermis

Schematic — not a tissue image

Slide 59 · Case 3: Interpreting an immunostain

The pale epidermal cells express CK7; Mucin can be highlighted by special stains.

Which cell lineage is supported?

Why must H&E and the clinical site still be reviewed?

Surface

Epidermis

Dermis

CK7-positive Paget cells

Slide 60 · Case 4: A lesion wider than it looks

Excision planning is challenged by microscopic Paget cells appearing beyond the grossly evident plaque.

Explain the mechanism of the mismatch.

What treatment rationale follows?

Pruritic erythematous plaque (schematic)

Slide 61 · Reporting priorities in a pathology discussion

Identify Paget cells and their intraepidermal distribution.

Record invasion status only when assessable in sampled tissue.

Communicate the relevance of lesion and margin extent.

Slide 62 · Frequent diagnostic reasoning errors

Calling an eczematous plaque benign from appearance alone.

Treating CK7 as infallibly specific without a differential.

Mistaking dermal inflammation for malignant invasion.

Assuming visible borders equal microscopic borders.

Slide 63 · Knowledge check: Interpret the observation

Observation

Most defensible inference

Isolated pale cells within vulvar epidermis

Consider Paget disease; Evaluate morphologic differential

PAS / Alcian blue / mucicarmine positivity

Supports mucinous cytoplasm

CK7 positive intraepidermal cells

Supports Paget phenotype in context

Malignant cells crossing into dermis

Invasive component; Higher concern

Slide 64 · Knowledge check: Choose the next step

Pruritic vulvar plaque persisting despite ordinary measures: Tissue evaluation rather than clinical assumption.

Pagetoid malignant cells with uncertain lineage: Appropriate lineage immunostains.

CK7-positive epidermal neoplasm: Examine H&E architecture and the underlying dermis.

Grossly confined plaque: Remember possible microscopic lateral extension.

Slide 65 · Core clinicopathologic synthesis

Vulvar pruritic / crusted plaque

Intraepidermal pale malignant cells

Mucin-containing cytoplasm + CK7

Microscopic lateral extension

Assess invasion and excision extent

Slide 66 · Selected source references

Robbins, Cotran & Kumar. Pathologic Basis of Disease. 11th ed. 2026. Chapter 22: The Female Genital Tract, pp. 902–903.

Robbins, Cotran & Kumar. 11th ed. 2026. Chapter 23: The Breast, pp. 952–953 (mammary comparison).

Cheng H, Lamont D. Extramammary Paget disease pathology. DermNet (2014). https://dermnetnz.org/topics/extramammary-paget-disease-pathology